Antimycotic diphenyl-imidazolyl-pyrimidyl methanes

ABSTRACT

N-methyl-imidazole derivatives of the formula:   OR A PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALT THEREOF, WHEREIN X is an unsubstituted or substituted six-membered heteroaromatic moiety having two nitro heteroatoms, Y is an unsubstituted or substituted aliphatic moiety, an unsubstituted or substituted cycloaliphatic moiety, an unsubstituted or substituted aralkyl moiety or an unsubstituted or substituted aryl moiety, and Z is an unsubstituted or substituted aliphatic moiety, an unsubstituted or substituted cycloaliphatic moiety, an unsubstituted or substituted aralkyl moiety, an unsubstituted or substituted aryl moiety, an unsubstituted or substituted pyridyl moiety or an alkoxycarbonyl moiety, ARE USEFUL AS ANTIMYCOTIC AGENTS.

United States Patent 191 Draber et al.

' 1 June 3, 1975 [73] Assignee: Bayer Aktiengesellschaft, Germany [22]Filed: Nov. 29, 1972 [21] Appl, No: 310,423

Related US. Application Data [62] Division of Scr. No. 120,333, March 2,1971, Pat.

[30] Foreign Application Priority Data Mar. 23, 1970 Germany 2013793[52] US. Cl... 260/2564 R; 260/250 R; 260/250 A; 260/2564 C; 260/2565 R;260/309;

[51] Int. Cl C07d 51/36 [58] Field ofsearchn. 260/2564 C, 256.4 R, 256.5R

[56] References Cited UNITED STATES PATENTS 3,048,587 8/1962 Oroshnik260/2564 3,381,015 4/1968 Shen et a1 260/295 Primary ExaminerD0nald G.Daus Assistant ExaminerRaymond V. Rush [57] ABSTRACT N-methyl-imidazolederivatives of the formula:

Y c NAN (I) or a pharmaceutically acceptable non-toxic salt thereof,wherein X is an unsubstituted or substituted six-membered heteroaromaticmoiety having two nitro heteroatoms,

Y is an unsubstituted or substituted aliphatic moiety, an unsubstitutedor substituted cycloaliphatic moiety, an unsubstituted or substitutedaralkyl moiety or an unsubstituted or substituted aryl moiety, and

Z is an unsubstituted or substituted aliphatic moiety, an unsubstitutedor substituted cycloaliphatic moiety. an unsubstituted or substitutedaralkyl moiety, an unsubstituted or substituted aryl moiety, anunsubstituted or substituted pyridyl moiety or an alkoxycarbonyl moiety,

are useful as antimycotic agents.

7 Claims, No Drawings ANTlMYCOTlC DIPHENYL-IMlDAZOLYL-PYRIMIDYL METHANESThis is a division of application Scr. No. 120,333 filed Mar. 2, 1971,now US Pat. No. 3,787,415.

The present invention is concerned with N-methylimidazole derivativesand their production as well as with pharmaceutical compositions,wherein said N- methyl-imidazole derivatives are the active ingredientand with methods of treating mycotic infections which comprisesadministering the N-methyl-imidazole derivatives of the presentinvention.

More particularly, the present invention is concerned withN-methyl-imidazole derivatives which are substituted at the methylcarbon atom by a six-membered heterocyclic moiety having two ringnitrogen atoms. These compounds are particularly useful for theirantimycotic and fungitoxic activity.

Some derivatives of six-membered heterocyclic compounds, which containtwo nitrogen atoms in the nucleus, are known. US. Pat. No. 2,839,446describes pyrimidies which carry a trichloromethylsulphonyl group in the2-position as being leaffungicides. Netherlands Pat. No. 6,806,106describes 5-substituted pyrimidines carrying a disubstituted ortrisubstituted methyl group as the substituent, it being possible forone of the substituents on this methyl group to be a hydroxyl, amino orphenylamino group. The pyrimidyldiaryl-carbinols, in particular,represent valuable systematic plant fungicides. These previously knowncompounds are however all exclusively active against plantpathogenicfungi and bacteria.

N-trityl-imidazole and substituted N-trityl-imidazoles are referred toin US. Pat. No. 3,321,366 as being useful against plant fungi.

The compounds of the present invention may be represented by theformula:

Y C N N wherein X is an unsubstituted or substituted six-memberedheteroaromatic moiety having two nitro heteroatoms,

Y is an unsubstituted or substituted alphatic moiety,

an unsubstituted or substituted cycloaliphatic moiety, an unsubstitutedor substituted aralkyl moiety or an unsubstituted or substituted arylmoiety, and

Z is an unsubstituted or substituted aliphatic moiety,

an unsubstituted or substituted cycloaliphatic moiety, an unsubstitutedor substituted aralkyl moiety, an unsubstituted or substituted arylmoiety, an unsubstituted or substituted pyridyl moiety or analkoxycarbonyl moiety,

and include pharmaceutically acceptable non-toxic salts thereof.

Among the heteroaromatic moieties for X are those of the formula:

which are bonded to the central carbon atom of formula (1) via a carbonatom in the ring and can either be unsubstituted or may be substitutedby one to three, and preferably one or two substituents which can eitherbe the same or different. Suitable substituents include halogen,particularly fluorine, chlorine and bromine, and especially chlorine,alkyl of one to four carbon atoms, and preferably one or two carbonatoms, alkoxy of one to four carbon atoms, and preferably one or twocarbon atoms or phenyl. Among the above alkyl and alkoxy substituentsare methyl, ethyl, npropyl,isopropyl, n-butyl, isobutyl, tert. butyl,particularly methyl and ethyl, and methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy and tert. butoxy, especially methoxy andethoxy. If X is a pyridazine ring, it is preferably bonded in the4-position to the central carbon atom. If R is a pyrimidine ring, it ispreferred that it be bonded in the 2- or 5-position to the centralcarbon atom.

When Y and/or Z are unsubstituted or substituted aliphatic moieties, itis preferred that such aliphatic moieties be straight or branched chainalkyl of one to six carbon atoms, and especially one to four carbonatoms, particularly methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl and tert. butyl, particularly methyl and tert. butyl. When suchaliphatic moieties are substituted, it is preferred that there be one ormore substituents, and preferably one or two substituents. Suitablesubstituents are alkyl of one to four carbon atoms, and preferably oneor two carbon atoms, alkoxy of one to four carbon atoms, and preferablyone or two carbon atoms, thioalkyl of one to four carbon atoms, andpreferably one or two carbon atoms, trifluoromethyl, halogen, especiallyfluorine, chlorine or bromine, nitro and cyano. Particular alkyl, alkoxyand thioalkyl moieties include methyl, ethyl, methoxy, ethoxy,methylmercapto, i.e., thiomethyl and ethylmercapto, i.e., thioethyl.

When X and/or Z are unsubstituted or substituted cy cloaliphaticmoieties, it is preferred that these have three to eight carbon atoms,and especially three to six carbon atoms. Cyclopropyl and cyclohexyl arepreferred moieties. When the cycloaliphatic moieties are substituted, itis preferred that there are one or more substituents and preferably oneor two substituents. Suitable substituents include alkyl of one to fourcarbon atoms, preferably one or two carbon atoms alkoxy of one to fourcarbon atoms, preferably one or two carbon atoms, thioalkyl of one tofour carbon atoms, preferably one or two carbon atoms, trifluoromethyl,halogen, especially fluorine, chlorine or bromine, nitro and cyano.Among the alkyl, alkoxy and thialkyl moieties are methyl, ethyl,methoxy, ethoxy, methylmercapto and ethylmercapto.

When Y and/or Z are unsubstituted or substituted aralkyl moieties, it ispreferred that these have six to 12 carbon atoms, and especially sixcarbon atoms in the aryl portion. and one to four carbon atoms, andespecially one or two carbon atoms in the alkyl portion. Benzyl andp-chlorobenzyl are among the preferred 'bon atoms, trifluoromethyl,halogen, especially fluosubstituents. When the aralkyl moiety issubstituted, there can be one or more substituents, preferably one ortwo. Substituents include alkyl of one to four carbon atoms, preferablyone or two carbon atoms, alkoxy of one to four carbon atoms, preferablyone or two carbon atoms, thioalkyl of one to four carbon atoms,preferably one or two carbon atoms, trifluoromethyl, halogen, especiallyfluorine, chlorine or bromine, nitro and cyano. Among the alkyl, alkoxyand thialkyl moieties are methyl, ethyl, methoxy, ethoxy, methylmercaptoand ethylmercapto.

When Y and/or Z are unsubstituted or substituted aryl moieties, it ispreferred that these have six to 10 carbon atoms, and especially sixcarbon atoms. When the aryl moiety is substituted, there can be one ormore substituents, preferably one or two. Substituents include alkyl ofone to four carbon atoms, preferably one or two carbon atoms, alkoxy ofone to four carbon atoms, preferably one or two carbon atoms, thioalkylof one to four carbon atoms, preferably one or two car- 3O rine,chlorine or bromine, nitro and cyano. Among the alkyl, alkoxy andthioalkyl moieties are methyl, ethyl, methoxy, ethoxy, methylmercaptoand ethylmercapto.

The preferred aryl moieties are phenyl, pfluorophenyl, o-chlorophenyl,o-methylphenyl, oisopropylphenyl, p-methoxyphenyl,m-trifluoromethylphenyl, m-nitrophenyl and naphthyl.

When Z is an unsubstituted or substituted pyridyl moiety, the pyridylmoiety is bonded in the 2-, 3- or 4- position to the central carbonatom. When the pyridyl moiety is substituted, it can contain one or moresubstituents, and preferably one or two substituents. Suitablesubstituents include alkyl of one to four carbon atoms, preferably oneor two carbon atoms, alkoxy of one to four carbon atoms, preferably oneor two carbon atoms, thioalkyl of one to four carbon atoms, preferablyone or two carbon atoms, trifluoromethyl, halogen, especially fluorine,chlorine and bromine, nitro and cyano. Among the alkyl, alkoxy andthioalkyl moieties are methyl, ethyl, methoxy, ethoxy, methylmercaptoand ethylmercapto. When Z is pyridyl, it is preferred that the pyridylmoiety be unsubstituted.

When Z is alkoxycarbonyl, it is preferred that there be one to fourcarbon atoms, and especially one or two carbon atoms, in the alkylmoiety. Methoxycarbonyl and ethoxycarbonyl are preferred.

Preferred salts of the compounds of the present invention are thosewhich are formed with pharmaceutically acceptable non-toxic acid, i.e.those which are physiologically well tolerated. Examples of such acidsare the hydrogen halide acids, such as for example bydrobromic acid andhydrochloric acid, phosphoric acids, sulphonic acids, monocarboxylic anddicarboxylic acids and hydroxycarboxylic acids. As examples of organicacids, acetic acid, tartaric acid, lactic acid, malic acid, citric acid,salicylic acid, sorbic acid and ascorbic acid may be mentioned.

Particularly preferred compounds are those of the formula (I) in which Xis a six-membered heteroaromatic ring of the formula:

Y is phenyl or p-fluorophenyl, and

Z is phenyl and pharmaceutically acceptable non-toxic thereof.

The compounds of the present invention can be produced according toseveral processes. According to one process, the compounds of thepresent invention are produced if a. a compound of the formula saltswherein X, Y and Z are as above defined, and

Hal is Cl or Br, is reacted with imidazole, optionally in the presenceof an acid acceptor or in the presence of an excess of imidazole in apolar organic solvent at temperatures between about 20 and about C, andthe salt is optionally manufactured, or b) a carbinol of the formula:

1- (l1-0H (III) X wherein X, Y and Z are as above defined, is reactedwith thionyldiimidazole of formula u Nso N p (IV) in an aprotic solvent,and the salt is optionally manufactured.

The starting compounds required for the manufacture of the new compounds(I) are known or are obtainable according to known processes.

The compounds (ll) can be manufactured in various ways. For example, itis possible to start from a carbinol (Ill) and to react this with ahalogenating agent, such as for example, thionyl chloride, thionylbromide, phosphoryl chloride, phosphoryl bromide, acetyl chloride oracetyl bromide, in solvents, such as for example ether, methylenechloride. benzene or toluene. It may at times also be appropriate tocarry out the halogenation in a polar solvent and to follow thisdirectly by the reaction with imidazole, without intermediate isolationof the halide formed. As polar organic solvents, acetonitrilenitromethane, dimethylformamide or hexamethylphosphoric acid triamidemay for example be mentioned.

A further process for the manufacture of'compounds of the formula (II),in which Hal is chlorine and X and Y are as above defined, comprisesreacting a ketone of the formula:

X H-Y in which X and Y are as above defined, firstly with PCI to give adichloride of the formula:

(II) consists of reacting a methane derivative of formula Y-- H (VII) inwhich X, Y and Z have the abovementioned meaning, with a halogenatingagent which operates by a radical mechanism, such as for exampleN-chlorophthalimide or N-bromosuccinimide, in an inert organic solvent,such as for example carbon tetrachloride.

The starting substances required for the processes indicated are knownor can be manufactured analogously to known processes. For example,Z-diphenylmethylpyrazine is obtained according to a method described byBehun et al., J. Org. Chem. 26, 3379 (1961). Further pyrazylcarbinolshave been described by Hirschberg, J. Heterocyclic Chem. 2, 209 (1965).Further. pyrazine derivatives which can be used as starting substancesof general formulae (II), (III) and (VII), in which X represents apyrazine radical, for the manufacture of compounds of formula (I), inwhich X is a pyrazine radical, are described in Netherlands Pat. No.105,432 and in German displayed specification No. 1,913,726.

Pyrimidine compounds of the formula (II), (III) and (VII), in which X ispyrimidine, used as starting substances, are also known or can bemanufactured according to processes which are in themselves known.Several processes are for example given in Chem. Ber. 93, 230 1960) andin Netherlands Pat. application No. 6,806,106.

Pyridazine compounds of the formula (II), (III) and (VII), in which X ispyridazine, can also be obtained in an analogous manner to thatdescribed in the abovementioned publications.

In process variant (a) the starting compound (II), the imidazole and theacid acceptor are employed in about molar amounts. If an excess ofimidazole is added as the acid acceptor, about 2 mols of imidazole mustbe used for this reaction. The reaction temperature is about 20 to about150 C, preferably about to about C.

As solvents in process (a), polar organic solvents, such as for examplelower alkylnitriles, such as for example acetonitrile,dimethylformamide, dimethylsulphoxide, lower alkylketones, such as forexample diethyl ketone, and hexamethyl phosphoric aicd triamide can beused.

Inorganic and organic bases can serve asacid acceptors. As inorganicbases, the alkali carbonates and alkaline earth carbonates, especiallypotassium carbonate and calcium carbonate, may for example be used. Asorganic bases, lower alkylamines, such as for example triethylamine, aswell as hetero-aromatic bases, such as for example pyridine and lutidinemay for example be used.

In process variant (b), the reactants (III) and (IV) are employed inabout molar amounts. Preferably, however, about 1 to about 2 mols ofthionyldiimidazole (IV) are employed per 1 mol of carbinol (III). Thereaction temperature is about 0 to about 100 C, preferably about 20 toabout 50 C.

The reaction (b) is generally carried out in inert organic solvents,such as for example lower alkylnitriles, such as for exampleacetonitrile, ethers, such as for example tetrahydrofurane anddiisopropyl ether, dimethylformamide or chlorinated hydrocarbons, suchas for example chloroform.

If 2-isopropyl-phenyl-2-pyrazyl-carbinol is used as the startingmaterial, the course of the reaction according to process (a) can berepresented by the following equation:

Qi---Cl HCl N .HCl l+3 Th'course of the reaction of process b) can berepresented by the following equation for the example of the reaction oftert.-butyl-phenyo--pyrimidyl-carbinol with thionyldiimidazole:

The following non-limitative examples more particularly illustrate thepresent invention.

EXAMPLE 1 C--CH Q-SG-Q of melting point 209C are obtained.

Analysis:

Calculated: C 76.9% H 5.2?! N 17.97: Found: C 77.3% H 5.6% N 18.0%

The thionyldiimidazole used for the reaction is ohtainable as follows:

40.8 g (0.6 mol) of imidazole dried over P 0; arc suspended in ml ofacetonitrile distilled over P 0 and treated, at 0 C, with 17.7 g (0.15mol) of freshly distilled thionyl chloride. The imidazole hydrochloridewhich has precipitated is rapidly filtered off and rinsed with 50 ml ofacetonitrile. The filtrate is immediately used for the reaction.

EXAMPLE 2 Diphenyl-pyrazyl-imidazoll -yl-methane.

26.2 g (0.1 mol) of diphenyl-pyrazyl-carbinol. melt- A $0 H-N r ingpoint 1 1 1 C, are treated with a solution of 0. 1 5 mol of thionyldiimidazole in 200 ml of dry acetonitrile and the mixture is heatedunder reflux for 1 hour. Thereafter it is concentrated, and theoily-crystalline residue is washed with water. 7.2 g ofa light browncrude product are obtained, which after recrystallisation from ether-/acetone yield 8.8 g (28 of theory) of a compound of the formula in theform of white crystals of melting point 198C.

EXAMPLE 3 4-Fluorophenyl-phenyl-pyrazyl-imidazol- 1 -yl-methane 28.0 g(0.1 mol) of 4-fluorophenyl-phenylpyrazylcarbinol together with asolution of 0.15 mol of thionylcliimidazole in 200 ml of acetonitrileare heated to the boil for one hour. Thereafter the mixture is filteredand concentrated, the residue is taken up in methylene chloride and thesolution is repeatedly extracted by shaking with water. The methylenechloride phase is dried and concentrated. A brown oil is obtained, whichis taken up in acetonitrile. After treating the solution with activecharcoal and filtering. dry hydrogen chloride is passed in untilsaturation is reached, and the precipitated product is filtered off andrinsed with acetonitrile and ether. 12.7 g (35% of theory) of thecompound of formula are obtained in the form of a yellow, hygroscopicpowder of melting point 86C (decomposition).

Analysis: CZUHISFNI Calculated: Found:

N 15.3% C N 14.8% C

EXAMPLE 4 and the darkbrown residue is washed with water and taken up inmethylene chloride. After drying with so dium sulphate, treating withactive charcoal and filter- Lil ing, the solution is concentrated. Theresidue is extracted by boiling with petroleum ether, and the mixture isfiltered and again concentrated. Finally. the material is recrystallisedfrom a little acetonitrile. 17.0 g (40% of theory) of the compound offormula are obtained in the form of orange-coloured crystals of meltingpoint 142- 146 C.

EXAMPLE 5 Diphenyl-pyrimid-2-yl-imidazoll-yl-methane 26.2 g (0.1 mol) ofdiphenyl-pyrymid-2-ylcarbinol are dissolved in ml of absoluteacetonitrile and treated with a solution of 0.15 mol ofthionyldiimidazole in 200 ml of acetonitrile. The mixture is stirred for1 hour at room temperature and subsequently heated to the boil for 10minutes. lt is then concentrated to about half its volume and dilutedwith ice water. The yellow oil which has precipitated is washed withwater, taken up in methylene chloride and the solution dried. Afterconcentration, a viscous residue remains which slowly crystallises. 16.0g (41% of theory) of the compound of formula are thus obtained, having amelting point of 1 38 143 C.

The following compounds wherein X, Y and Z of the below set forthformula areas indicated, are produced in a manner analogous to that ofthe preceding examples from the reactants set forth in the table whichfollows:

. Table .Exanlple process a) process b) (,see pages 7-8) (see ,pages7-8) No. reactants: reactants: ,7 A Q {)1 so Na B A B Z (meaning ofX,Y,Z 6 Y I Cl for each example Y C Z OH a x see p ges 17 19) X 12 I I ru r- 13 Y Br I:

A l 20 II I l 21 y c1- I 27 I l l As alrea y mentioned. the newCompounds how an Minimal inhibitory cnneentrutiun (MIC) t t e in 'y/mlnlsu ISII'ZIIC exeelle nt amp m wtlc flCtlllty, as can be seen from theCom Tmhw Micm Candid Aspen Punk followmg 1n vltro and m vlvoexperiments: pmmd l 1, 11 in in vitro from phymn spurun nlhieuns glllusell rum Ann m) C Ct 615 example memul'elineum mger commune gmphytes TheTable summarises the unti-mycotic actions in 3 4 m 40 m 40 vitro ofseveral preparations towards several species of i i y fungi:

The MIC determination was carried out in a serial dilution test. in thedilution series"l()()-4()2(l-l(l4-l y/ml of substrate. The followingwere used as nutrient substrates:

a. for Dermatophytes: Sabouraud's test medium b. for yeasts: meat waterglucose bouillon. The incubation temperature was 2t C. and theincubation time was 24 to 9o'hours.

The preparatons are primarily fungistatic: fungicidal effects can beachieved in vitro with four-fold to six fold higher MIC concentrations.

The in vitro experiments were also carried out with the compounds fromExamples 1, 2 and 3, which can be regarded as representative of theentire class of compounds.

b. Anti-mycotic action in vivo l. Experimental canidosis in mice Whitemice strain CF -SPF, pellet fodder. water ad libitum were eachintravenously infected with l 5 X Candida ulbicuns cells. Untreatedcontrol animals died 3 to 6 days after infection to the extent of 95%from uraemia through multiple abscess formation in the kidneys.

In the case of oral and/or parenteral therapy with the preparationsmentioned especially with the compound from example 3 in daily doses of50 to 200 mg/kg of body weight. divided into two individual doses, 60 to90% of the animals survived on the 6th day after the infection. In theseexperiments. the therapy was started on the day of the infection andcontinued up to the 5th day after infection.

The preparations are rapidly resorbed after oral administration. Bloodlevel maxima, with concentrations of up to 6 'y/mg of serum, are reached4 to 5 hours after administration.

2. Experimental trichophytia in mice, caused by Triclwphymn Quinckuemun.

White CF -SPF mice were infected dorsally with a spore suspension ofTricliopliymri QllilZ('k(l()lll/71. After 8 to 10 days typical. multiplecups developed in the untreated control animals.

By means of daily doses of 50 to 200 mg/kg of body weight, divided intotwo individual doses and administered orally from the day of infectionup to the 8th day after infection. it was possible completely tosuppress the occurrence of the cups typical of the infection in infectedanimals.

3. Experimental trichophytia in guinea pigs caused by Tric/topltytonmentagrophytes.

Guinea pigs Pearlbright white, weighing 400 to 500 g. were infected ontheir shaved back with a spore suspension of Trichophyton menmgrophytes.A deep dermatomycosis developed at the point of infection within 21 to25 days, and continued up to the th- 34th day after infection.

In the case of animals which were treated locally with a 1% strengthsolution of the preparations in polyethylene glycol 400, once daily fromthe 3rd day after infection to the l4th day after infection, theinfection completely healed within the therapy time..Non-tolerancereactions by the skin were not observable in these experiments.-

According to these results. the preparations mentionedcan be regarded asgood anti-mycotic agents of broad-activity. which are euratively activeboth in oral and parenteral administration and in local administrationin animal experiments.

The excellent antianycotic activity of the new compounds makcs itpossible to employ them in the whole of human medicine and veterinarymedicine.

The following are envisaged as indications for the new preparations:

1. in human medicine:

Dermatomycoses by Dermatophytes, for example varieties of Trichophyton,Microsporon and Epidermophyton, systemic and organic mycoses by, forexample, varieties of Candida, Histoplasma, Cryptococcus andCoccidiodies. Aspergilli and other moulds.

2. in veterinary medicine:

Dermatomycoses as well as organic mycoses and systemic mycosses causedby Dermatophytes. yeasts, biphase fungi and moulds.

The new compounds can be administered orally, parenterally or locally,as free bases or in the form of their salts with physiologicallytolerated acids.

In general. it has proved advantageous to administer amounts of about 30mg to about 200 mg. preferably about 50 to 100 mg, per kg of body weightper day, to achieve effective results. Nevertheless it can at times benecessary to deviate from the amounts mentioned, in particular dependingon the body weight of the test animal or patient, the nature of themethod of administration, and severity of the condition as well asbecause of the species of animal and its individual behavior towards themedicine. or the patients past medical history, or the nature of theformulation and the point in time or interval at which theadministration takes place. Thus it can suffice in some cases to useless than the above-mentioned minimum amount, while in other cases theupper limit mentioned must be exceeded. Where larger amounts areadministered it can be advisable to divide these into several individualadministrations over the course of the day. The same dosage range isenvisaged for administration in human medicine. The other comments madeabove also apply, in a general sense.

The compounds of the present invention may be formulated intopharmaceutical compositionswhich comprise a compound according to thepresent invention in combination with a pharmaceutically acceptablenontoxic inert diluent or carrier. Possible forms for administration, incombination with various inert excipients, are tablets, capsules,powders, sprays, aqueous suspensions, injectable solutions, elixirs,syrups and the like. Such excipients include solid diluents or fillers,a sterile aqueous medium and also various non-toxic organic solvents andthe like. Of course the tablets and the like considered for oraladministration can be provided with a sweetener additive and thelike.The therapeutically active compound should. in the abovementioned case.be present at a concentration of about 0.5 to 90 percent by weight ofthe total mixture, that is to say in amounts which suffice to achievethe abovementioned dosage range.

starch and the like. and binders such as polyvinylpyrrolidone. gelatinesand the like. Furthermore, lubricants such as magnesium stearate, sodiumlauryl sulphate and talc can be conjointly used for tabletmaking. In thecase of aqueous suspensions and/or elixirs which are intended for oraluses. the active substance can be used together with variousflavourimproving agents. dyestuffs and emulsifiers and/or togcther withdiluents such as water. ethanol. propylene glycol or glycerine andsimilar compounds or combinations of this nature.

In the case of parenteral use. solutions of the active substances insesame oil or groundnut oil or in aqueous propylene glycol ofN.N-dimethylformamide can be employed. as can sterile aqueous solutionsin the case of the water-soluble compounds. Such aqueous solutionsshould be buffered in the usual manner where required, and furthermorethe liquid diluent should beforehand be rendered isotonic by addition ofthe requisite amount of salt or glucose. Such aqueous solutions are inparticular suitable for intravenous. intramuscular and interperitonealinjections.

The manufacture of such sterile aqueous media is carried out in a knownmanner.

The compounds are used locally in the form of 0.5 to strength,preferably 1'7: strength, solutions (for example in dimethylformamide.glycerine or water, alcohol such as ethanol and isopropanol. and buffersolu tions). but also as emulsions. suspensions, powders and tablets.

In general, therefore, the invention also provides a pharmaceuticalcomposition comprising as active ingredient at least one of the newactive compounds in admixture with a pharmaceutically acceptablenontoxic inert solid or liquid diluent or carrier.

The invention further provides a medicament in unit dosage formcomprising as active ingredient at least one of the new active compoundseither alone or in admixture with a pharmaceutically acceptablenon-toxic inert solid or liquid diluent or carrier. The medicament mayinclude a protective envelope containing the active compound and, ifused. the diluent or carrier.

The term medicament in unit dosage form" as used in the presentspecification means a medicament as defined above in the form ofdiscrete portions each containing a unit dose, or a multiple orsub-multiple of a unit dose of the active compound or compounds.especially a half, a third or a quarter of a unit dose, or two, three orfour unit doses. Such portions may. for example, be in monolithiccoherent form, such as tablets, suppositories, pills or dragees; inwrapped or concealed form, such as wrapped powders, cachets, sachets orcapsules; in ampoules, either free or as a sterile solution suitable forparenteral injection; or in any other form known to the art.

What is claimed is:

l. A compound of the formula:

wherein X is 20 N N N u or V Y is phenyl or p-fluorophenyl. and Z isphenyl. 2. The compound according to claim 1, which is 4. The compoundof the formula:

Y (ii-11 wherein N X is Y is 5. The compound of the formula.

6. The compound of the formula:

if L] wherein and Zis @4' 7. The compound of the formula:

l gn wherein and Zis

8. The compound according to claim 5 of the

1. A COMPOUND OF THE FORMULA:
 1. A compound of the formula:
 2. Thecompound according to claim 1, which is
 3. The compound according toclaim 1, which is
 4. The compound of the formula:
 5. The compound of theformula:
 6. The compound of the formula:
 7. The compound of the formula: